a brain on cannabinoids: the role of dopamine release in...

A Brain on Cannabinoids: The Role of DopamineRelease in Reward Seeking

Erik B. Oleson1 and Joseph F. Cheer1,2

1Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore,Maryland 21201

2Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland 21201

Correspondence: [email protected]

Increases in mesolimbic dopamine transmission are observed when animals are treated withall known drugs of abuse, including cannabis, and to conditioned stimuli predicting theiravailability. In contrast, decreases in mesolimbic dopamine function are observed duringdrug withdrawal, including cannabis-withdrawal syndrome. Thus, despite general miscon-ceptions that cannabis is unique from other drugs of abuse, cannabis exerts identical effectson the mesolimbic dopamine system. The recent discovery that endogenous cannabinoidsmodulate the mesolimbic dopamine system, however, might be exploited for the develop-ment of potential pharmacotherapies designed to treat disorders of motivation. Indeed,disrupting endocannabinoid signaling decreases drug-induced increases in dopaminerelease in addition to dopamine concentrations evoked by conditioned stimuli duringreward seeking.

All known drugs of abuse, including D9-tet-rahydrocannabinol, the primary psychoac-

tive component of Cannabis sativa, increasedopamine concentrations in terminal regionsof the mesolimbic dopamine system (Di Chiaraand Imperato 1988; Pierce and Kumaresan2006). The mesolimbic dopamine system is aneural pathway that originates from A10 dopa-mine neurons in the ventral tegmental area ofthe midbrain and projects to limbic structures,most prominently the nucleus accumbens (Ta-ble 1) (Spanagel and Weiss 1999). Increases innucleus accumbens dopamine are theorized tomediate the primary positive reinforcing andrewarding properties of all known drugs ofabuse (Roberts et al. 1977; Wise and Bozarth

1985; Ritz et al. 1987). In addition, when ani-mals are presented with conditioned stimulithat predict drug availability, transient dopa-mine events that are theorized to mediate thesecondary reinforcing effects of drugs of abuseand initiate drug seeking are also observedin the nucleus accumbens (Phillips et al. 2003;Owesson-White et al. 2009). In contrast, thenegative affective state that occurs during drugwithdrawal is associated with a decrease inmesolimbic dopamine function, which mightlead to compulsive drug seeking (Weiss et al.2001; Koob 2009). This article reviews studiesaddressing the effects of cannabinoids andcannabinoid withdrawal on dopamine release,in addition to the effects of manipulating the

Editors: R. Christopher Pierce and Paul J. Kenny

Additional Perspectives on Addiction available at www.perspectivesinmedicine.org

Copyright # 2012 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a012229

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endogenous cannabinoid system on drug- andcue-evoked dopamine release.

TONIC AND PHASIC DOPAMINE OVERVIEW

Before delving into the interaction between can-nabinoids and the dopamine system, it is im-portant first to develop a general understandingof the patterns of dopamine signaling and thecommon methods used to monitor dopaminetransmission in vivo. Two distinct patterns ofdopamine neural activity occur in the behavinganimal. Midbrain dopamine neurons typically

fire at low frequencies of 1–5 Hz, which isthought to produce a tone on high-affinity dop-amine D2 receptors in terminal regions of themesolimbic dopamine system, including thenucleus accumbens (Grace 1991; Dreyer et al.2010). These tonic dopamine levels are detect-able using techniques, such as in vivo micro-dialysis, that allow for neurochemical collectionon a timescale of minutes. In contrast, whenanimals are presented with motivationally sa-lient stimuli, such as conditioned cues that pre-dict drug availability, midbrain dopamine neu-rons fire in high-frequency bursts (�20 Hz),

Table 1. Terminology and definitions used in text

Terminology Definition

Cannabinoids Pharmacologically defined as a class of chemical compounds—comprisingphytocannabinoids, chemically synthesized cannabinoids, andendocannabinoids—that bind to the cannabinoid CB1/CB2 receptor.

Primary reinforcer An event that increases the probability of a behavioral response. In the contextof drug addiction, an injection of heroin or a toke on a pipe might functionas a primary reinforcer.

Secondary reinforcer Also referred to as a “conditioned cue,” a stimulus that acquires reinforcingproperties through Pavlovian associations. In the context of drug addiction,a syringe or a pipe might function as a secondary reinforcer.

Negative reinforcer An event that increases the probability of a behavioral response resulting in theelimination or avoidance of the event.

Tonic dopamine A steady-state dopamine level arising from dopamine neurons firing at lowfrequency (1–5 Hz) that is capable of occupying high-affinity dopamineD2 receptors.

Phasic dopamine A significant, transient increase in dopamine concentration arising fromdopamine neurons firing in high-frequency bursts (�20 Hz) that is capableof occupying low-affinity dopamine D1 receptors.

Microdialysis In the context of in vivo neurochemistry, a semipermeable probe is insertedinto a brain region, artificial cerebral spinal fluid is infused, and dialysatecontaining neurotransmitters that passively diffuse into the probe isextracted and analyzed.

Fast-scan cyclicvoltammetry (FSCV)

In the context of in vivo neurochemistry, a carbon fiber microelectrode isinserted into a brain region, and voltage is applied to the carbon fiber,resulting in the oxidation of surrounding chemicals; the resulting currentflow is detected and analyzed.

Nucleus accumbens A component of the basal ganglia that is commonly divided into twosubstructures, the core and the shell. All known drugs of abuse increasedopamine concentrations in the nucleus accumbens.

Ventral tegmental area A group of neurons within the midbrain that are primarily dopaminergic(.50%) and contribute to the mesocortical and mesolimbic dopaminepathways.

Mesolimbic dopaminesystem

A dopaminergic pathway in the brain that projects from A10 dopamineneurons in the VTA to limbic structures including the nucleus accumbens,amygdala, hippocampus, and medial prefrontal cortex.

E.B. Oleson and J.F. Cheer

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thereby producing transient increases in nucle-us accumbens dopamine concentration that aresufficiently high to occupy low-affinity dopa-mine D1 receptors (Grace 1991; Phillips et al.2003; Dreyer et al. 2010). These phasic dopa-mine events are detectable in vivo at the levelof the dopamine neuron using single-unit elec-trophysiological recording techniques or at theneurochemical level within terminal fields of themesolimbic dopamine system using fast-scancyclic voltammetry, an electrochemical tech-nique that allows for the detection of dopamineon the millisecond timescale.

CANNABINOIDS INCREASE TONICDOPAMINE LEVELS

A long-held misconception was that cannabi-noids, such as D9-tetrahydrocannabinol, fail toincrease dopamine concentrations in the samemanner as other drugs of abuse (Wickelgren1997). This point was even disputed in the ex-perimental literature; for example, a single edi-tion of the journal Pharmacology, Biochemistry,and Behavior contained contrasting reports onwhether cannabinoids increase dopamine levelsin the brain (cf. Gardner and Lowinson 1991vs. Castaneda et al. 1991). Currently, however,the existence of an overwhelming body of neu-rochemical evidence (Ng Cheong Ton et al.1988; Chen et al. 1990, 1991, 1993; Tanda et al.1997; Malone and Taylor 1999) unequivocallyshows that cannabinoids do, indeed, increasedopamine concentrations in the nucleus ac-cumbens. It should be noted, however, that ge-netic factors partially determine the magnitudeof cannabinoid-induced increases in accumbaldopamine concentration (Gardner 2002, 2005),because Gardner and colleagues (Chen et al.1991) reported that the dopamine-increasingpotency of cannabinoids varies depending onthe strain of rat assessed. Importantly, thesecannabinoid-induced increases in nucleus ac-cumbens dopamine are most prominentlyobserved in the shell region of the nucleus ac-cumbens and occur in a cannabinoid CB1 re-ceptor-dependent manner. As illustrated in Fig-ure 1A, the cannabinoid CB1 receptor agonistWIN55,212-2 increased dopamine concentra-

tions within the nucleus accumbens shell, aneffect that was blocked by the coadministrationof the cannabinoid CB1 receptor antagonist ri-monabant. Cannabinoid-induced increases innucleus accumbens dopamine concentrationare thought to arise from an increase in themean firing rate of dopamine neurons withinthe ventral tegmental area. In accordance withthis theory, using single-unit recording tech-niques, multiple reports indicate that cannabi-noids increase the firing rate of ventral tegmentalarea dopamine neurons (French 1997; Frenchet al. 1997; Gessa et al. 1998; Wu and French2000). These parallel increases in cannabinoid-induced neural activity are shown in Figure 1B;specifically, WIN55,212-2 dose-dependently in-creased the frequency of dopamine neural firing(Gessa et al. 1998). Importantly, also, the canna-binoid-induced increases in dopamine neuralactivity were abolished following administrationof rimonabant, which shows that cannabinoidsincrease dopamine neural activity through aCB1 receptor-dependent mechanism.

CANNABINOIDS INCREASE PHASICDOPAMINE EVENTS

The majority of the aforementioned neuro-chemical studies measured changes in tonicdopamine levels using in vivo microdialysis.To assess whether cannabinoids increase phasicdopamine release events, Cheer et al. (2004)measured nucleus accumbens dopamine con-centrations in the behaving rat using fast-scancyclic voltammetry. As illustrated in Figure 1C,WIN55,212-2 increased the frequency of phasicdopamine events detected in the nucleus ac-cumbens shell (Cheer et al. 2004). Rather thanresulting from the regular pacemaker firing thatcharacterizes tonic dopamine signaling (e.g.,Fig. 1B), these transient increases in accumbaldopamine release are thought to arise fromhigh-frequency bursts of dopamine neural ac-tivity (Gonon 1988; Sombers et al. 2009). Aswould be predicted, therefore, Figure 1D showsthat the cannabinoids D9-tetrahydrocannabinoland WIN55,212-2 both increased the frequencyof bursts in addition to the number of impulses

Cannabinoids, Dopamine, and Addiction

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occurring during each burst of dopaminergicneural activity (Gessa et al. 1998).

PHARMACOLOGICAL MECHANISMSOF CANNABINOID-INDUCED INCREASESIN DOPAMINE

After determining that cannabinoids increaseboth tonic and phasicdopamine neurotransmis-

sion, investigators began addressing the phar-macological mechanisms involved. Initially, invitro synaptosomal studies suggested that can-nabinoids might increase nucleus accumbensdopamine concentrations, in part, by bindingto the dopamine transporter and thereby de-creasing uptake into presynaptic terminals(Hershkowitz and Szechtman 1979; Poddarand Dewey 1980), which would be consistent

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Figure 1. Cannabinoids increase tonic and phasic dopamine release. (A) The cannabinoid CB1 receptor agonistWIN55,212-2 (0.3 mg/kg i.v., filled circles) increased tonic dopamine concentrations in the shell region of thenucleus accumbens in comparison to vehicle (open parallelograms). The cannabinoid CB1 receptor antagonistrimonabant (1 mg/kg s.c., open triangles) prevented the WIN-induced increase in accumbal dopamine con-centration. (Figure constructed from data by Tanda et al. 1997.) (B) WIN55,212-2 dose-dependently increasedthe neural activity of an antidromically identified ventral tegmental area dopamine neuron. Rimonabantreversed the WIN-induced increase in dopamine neural activity. (Figure constructed from data by Gessaet al. 1998.) (C) WIN55,212-2 (0.125 mg/kg i.v., right of dashed line) increased the frequency of phasicdopamine events detected in the shell region of the nucleus accumbens in comparison to pre-treatment (leftof dashed line) values. To assess for cannabinoid-induced changes in dopamine uptake, dopamine release wasevoked by electrical stimulation (0.4-sec duration, 60 Hz, +120 mA, black bars) applied to the medial forebrainbundle. WIN55,212-2 failed to increase the width of electrically evoked dopamine events, suggesting thatcannabinoids do not increase nucleus accumbens dopamine by decreasing dopamine uptake. (Figure construct-ed from data by Cheer et al. 2004.) (D)D9-Tetrahydrocannabinol (filled bars) and WIN55,212-2 (open bars withcoarse diagonal fill) increased phasic dopamine neural activity. Both cannabinoids increased the number ofbursting events observed and the number of impulses occurring per burst. (�) A significant difference versus pre-drug levels. (Figure constructed from data by Gessa et al. 1998.)



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with the pharmacological mechanism of actionof other drugs of abuse, such as cocaine. If can-nabinoids increase dopamine concentration bydecreasing uptake, however, the width of electri-cally evoked dopamine release events should in-crease when assessed using in vivo FSCV. Electri-cally evoked dopamine events result in highconcentrations of dopamine that saturate dopa-mine transporters, thus allowing changes in up-take to be discerned. As illustrated in Figure 1C,cannabinoids failed to alter the width of electri-cally evoked dopamine release events, therebyshowing that cannabinoids do not increase dop-amine by decreasing uptake (Cheer et al. 2004).Furthermore, dopamine uptake inhibitors typi-cally decrease neural firing of dopamine neuronsby activating inhibitory dopamine D2 autore-ceptors (Einhorn et al. 1988). Thus, a cannabi-noid-induced decrease in dopamine uptakewould be inconsistent with a cannabinoid-in-duced increase in dopamine neural firing (Fig.1B). Another possibility is that cannabinoidsmight directly stimulate dopamine neurons;however, this hypothesis is also unlikely, becauseof multiple reports that dopamine cell bodieslack cannabinoid CB1 receptors (Herkenhamet al. 1991; Julian et al. 2003). An alternativemodel, proposed by Carl Lupica (Lupica andRiegel 2005), suggests that cannabinoids mightincrease dopamine release by indirectly disin-hibiting dopamine neurons. In support of thismodel, application of cannabinoids to ventraltegmental area brain slices decreased GABAergicinhibitory postsynaptic currents in a GABAA re-ceptor-dependent manner (Szabo et al. 2002)and failed to increase dopamine neural activityfollowing pre-treatment of GABAA receptor an-tagonists (Cheer et al. 2000). Taken together, insupport of Lupica’s model, these data suggestthat cannabinoids increase dopamine neural fir-ing by decreasing GABAergic inhibition of dop-amine neural activity.

DOPAMINE LEVELS ARE DECREASEDDURING CANNABIS WITHDRAWAL

A key feature of the addiction phenomenon—drug withdrawal—is theorized to produce anegative emotional state that drives persistent,

relapsing drug seeking (Childress et al. 1988;Koob et al. 1998). It is now well accepted thatwithdrawal occurs in association with a decreasein mesolimbic dopamine function (Weiss et al.2001). For example, when experimental animalsare withdrawn from drugs of abuse (e.g., etha-nol, morphine, cocaine, and amphetamine),decreased tonic dopamine concentrations aredetected in the terminal regions of the meso-limbic dopamine system when assessed using invivo microdialysis (Rossetti et al. 1992; Weisset al. 1992, 1996). Although the use of cannabi-noids, such as marijuana and hashish, was his-torically considered to be devoid of withdrawalsymptoms (Todd 1946), we now know thatcannabinoids do, indeed, produce clinically sig-nificant withdrawal symptoms. Over the courseof several clinical studies (Jones et al. 1976;Budney et al. 1999; Haney et al. 1999), in-vestigators documented a “cannabis-withdraw-al syndrome,” which is composed of several coresymptoms, including anxiety/nervousness, de-creased appetite/weight loss, restlessness, sleepdifficulties including strange dreams, chills,depressed mood, stomach pain/physical dis-comfort, shakiness, and sweating (Budney andHughes 2006). It is likely, therefore, that thesewithdrawal symptoms contribute to cannabisdependence through negative reinforcementprocesses. The development of animal modelsof cannabis-withdrawal syndrome allowed forthe investigation of the neural mechanisms in-volved. To date, two distinct models of cannabiswithdrawal exist (Lichtman and Martin 2002).The first, involving abrupt forced abstinencefrom experimenter-administered cannabinoids(e.g., D9-tetrahydrocannabinol, WIN55,212-2),results in mild withdrawal symptoms that arerelatively difficult to detect (Aceto et al. 1996,2001). The second, involving precipitated with-drawal induced by a rimonabant challenge,results in immediately observable robust with-drawal symptoms (e.g., wet dog shakes) (Acetoet al. 1995; Tsou et al. 1995). The behavior-al manifestations of precipitated cannabinoidwithdrawal are accompanied by a decrease inventral tegmental dopamine neural activity asassessed using single-unit recording techniques(Diana et al. 1999). The decreased dopamine



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neural activityoccurs along the same time courseas decreased tonic dopamine concentrations ob-served in the nucleus accumbens using in vivomicrodialysis (Tanda et al. 1999). Precipitatedwithdrawal also induces a significant decreasein phasic dopamine neural activity (Dianaet al. 1999). Taken together, these studies showthat withdrawal from cannabinoids depressesmesolimbic dopamine function in the samemanner as other drugs of abuse.

A BRIEF INTRODUCTION TO THEENDOCANNABINOID SYSTEM

The isolation of D9-tetrahydrocannabinol fromC. sativa (Gaoni and Mechoulam 1964), thediscovery that D9-tetrahydrocannabinol bindsto a G-protein-coupled receptor in the brain(Devane et al. 1988), and the subsequent clon-ing of the cannabinoid CB1 receptor (Matsudaet al. 1990) led to the elucidation of a pre-viously uncharacterized endogenous cannabi-noid, or endocannabinoid system. Anandamide(Devane et al. 1992) and 2-arachydonoylglcy-cerol (Mechoulam et al. 1995) were the first, andremain the best, characterized endocannabi-noids. Based on a growing recognition that can-nabinoids modulate mesolimbic dopaminefunction, the endocannabinoid system is cur-rently receiving a great deal of attention as in-vestigators search for potential pharmacothera-pies for addiction (Vries and Schoffelmeer2005; Justinova et al. 2009).

ENDOCANNABINOIDS MIGHT INCREASEDOPAMINE RELEASE BY DISINHIBITINGDOPAMINE NEURAL ACTIVITY

Lupica’s model (Lupica and Riegel 2005) con-cerning cannabinoid modulation of dopamineneural activity is also relevant in the contextof endocannabinoid signaling. Endocannabi-noids are unique from classical neurotransmit-ters in that they are formed and released ondemand during periods of high neural activity(Freund et al. 2003). Thus, during phasic dop-amine events, intracellular Ca2þ increases pre-cipitously, which then activates enzymes (e.g.,diaacylglycerol lipase, DGL) leading to the syn-

thesis of endocannabinoids (Wilson and Nicoll2002; Melis et al. 2004; Alger and Kim 2011).Once synthesized, endocannabinoids traversethe plasma membrane into the extra-synapticspace, where they retrogradely activate cannabi-noid CB1 receptors on presynaptic terminals(Wilson and Nicoll 2001). Endocannabinoidsbinding to presynaptic cannabinoid CB1 recep-tors is known to result in the suppression ofGABA-mediated inhibition (Wilson and Nicoll2001), a form of synaptic plasticity known asdepolarization-induced suppression of inhibi-tion (Alger and Kim 2011). Within the ventraltegmental area, depolarization-induced sup-pression of inhibition should theoretically re-sult in a net disinhibition of dopamine neuralactivity (cf. Fig. 2, A vs. B) (Lupica and Riegel2005). A growing body of evidence suggests that2-arachydonoylglycerol is the primary endo-cannabinoid involved in mediating such formsof synaptic plasticity (Melis et al. 2004; Tani-mura et al. 2010).

DISRUPTING ENDOCANNABINOIDSIGNALING DECREASES DRUG-INDUCEDINCREASES IN PHASIC AND TONICDOPAMINE SIGNALING

All drugs of abuse increase phasic dopamineevents, which theoretically promote drug seek-ing (Cheer et al. 2007; Aragona et al. 2008).Decreasing drug-induced phasic dopamineevents by disrupting endocannabinoid signal-ing might, therefore, prove to be a successfulpharmacological approach for the treatmentof addiction (Vries and Schoffelmeer 2005;Solinas et al. 2008). To test whether disruptingendocannabinoid signaling decreases drug-in-duced phasic dopamine events, Cheer et al.(2007) monitored drug-induced increases inphasic dopamine release events in the nucleusaccumbens shell using fast-scan cyclic voltam-metry. All drugs assessed, including cocaine,nicotine, and ethanol, increased the frequencyof phasic dopamine events. Remarkably, disrup-ting endocannabinoid signaling by coadmin-istering rimonabant attenuated these drug-in-duced increases in phasic dopamine release.As illustrated in Figure 3C, cocaine-induced



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increases in phasic dopamine events (top) werediminished by rimonabant (middle) and notobserved following vehicle administration alone(bottom). If disrupting endocannabinoid sig-naling decreases drug-induced phasic dopa-mine events by preventing the disinhibition of

dopamine neural activity within the ventral teg-mental area, it should be predicted that tonicdopamine signaling also be suppressed. In ac-cordance with this theory, ethanol-induced in-creases in tonic accumbal dopamine concentra-tions are blocked by rimonabant (Hungund

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Figure 2. A theoretical microcircuit within the ventral tegmental area showing GABAergic and glutamatergicterminals synapsing onto a dopamine neuron. (A) Under typical conditions, ventral tegmental area dopamineneurons are inhibited via activation of GABAB receptors on the dopaminergic neuron. (B) When animals arepresented with motivational salient stimuli (e.g., a drug-associated cue), dopamine neurons fire in high-frequency bursts. Consequently, intracellular calcium levels increase, which results in the activation of endo-cannabinoid synthesizing enzymes (e.g., diacylglycerol lipase, DGL). As a result, 2-arachydonoylglycerol (2-AG)is synthesized and released into the extrasynaptic space. By retrogradely activating Gi/o-coupled cannabinoidCB1 receptors on GABAergic terminals, GABA release is suppressed. This GABA suppression results in dis-inhibition of the dopamine neuron, which presumably promotes the occurrence of phasic dopamine events.



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et al. 2003). These findings are in agreement withthe electrophysiology literature. For example,Pistis and colleagues (Perra et al. 2005) showedthat ethanol-induced increases in dopamineneural activity are reduced following rimona-bant treatment. Together, these findings supportthat developing drugs designed to disrupt endo-cannabinoid signaling might decrease drug-in-duced increases in phasic dopamine release,which is thought to promote drug seeking, inaddition to tonic dopamine release, which is

thought to mediate the primary rewarding andreinforcing effects of drugs of abuse.

DISRUPTING ENDOGENOUSCANNABINOID SIGNALING DECREASESCUE-EVOKED DOPAMINE RELEASE

It is now well accepted that Pavlovian associa-tions formed between drugs of abuse andenvironmental cues may trigger drug seeking(Childress et al. 1993). In this context, phasic

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Figure 3. Endocannabinoids are necessary for drug-induced increases in tonic and phasic dopamine release. (A)Endocannabinoids are required for ethanol-induced increases in tonic dopamine concentrations in the nucleusaccumbens. When administered independently, ethanol (1.5 g/kg, filled squares) increased dopamine concen-trations. When coadministered with rimonabant (3 mg/kg i.p., open triangles), ethanol failed to increaseaccumbal dopamine concentrations. (Figure constructed from data by Hungund et al. 2003.) (B) Disruptingendocannabinoid signaling with rimonabant (1 mg/kg i.v., bottom) reversed ethanol-induced (0.5 g/kg i.v.,top) increases in the neural activity of an antidromically identified ventral tegmental area dopamine neuron.(Figure constructed from data by Perra et al. 2005.) (C) Endocannabinoids are required for drug-induced phasicdopamine events. Cocaine (3 mg/kg i.v., top) significantly increased transient increases in nucleus accumbensdopamine concentration. Rimonabant coadministration (0.3 mg/kg i.v., middle) significantly attenuated thecocaine-induced increases in phasic dopamine release. Vehicle alone failed to alter phasic dopamine events(bottom). (Figure constructed from data by Cheer et al. 2007.)



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dopamine events are thought to encode con-ditioned stimuli and promote drug seeking(Wheeler and Carelli 2009). It is possible, there-fore, that disrupting endocannabinoid signal-ing might effectively diminish the influencethat environmental cues exert over dopaminetransmission during reward-directed behavior.A current theory holds that endocannabinoidsdecrease drug-seeking behavior, in part, bydiminishing the secondary/environmental in-fluences of drugs on motivated behavior (LeFoll and Goldberg 2004; Vries and Schoffel-meer 2005). For example, when responding ismaintained by drug-associated environmentalcues under second-order schedules of reinforce-ment, rimonabant significantly decreases drugseeking (Justinova et al. 2008). Furthermore,endocannabinoid disruption is particularly ef-fective at reducing cue-induced reinstatement,a model of relapse in humans that incorporatesthe influence of conditioned environmentalstimuli on reward seeking (Epstein et al. 2006).Indeed, rimonabant decreases the propensity forconditioned cues to reinstate responding forvarious drugs of abuse (Vries and Schoffelmeer2005; Justinova et al. 2008). To assess whetherdisrupting endocannabinoid signaling decreasescue-evoked dopamine signaling, Cheer and col-leagues (Oleson et al. 2012) treated rats withrimonabant while responding was maintainedby brain stimulation reward in a cued intracra-nial self-stimulation task. Under these condi-tions, rimonabant significantly decreased cue-evoked dopamine release and reward seeking inunison, thereby suggesting that endocannabi-noids are critical modulators of dopamine trans-mission during cue-motivated behavior.

2-ARACHYDONOYLGLYCEROL ANDANANDAMIDE MIGHT DIFFERENTIALLYREGULATE DOPAMINE SIGNALINGDURING CUE-MOTIVATED BEHAVIOR

Although rimonabant clearly decreases dopa-mine signaling during cue-motivated behavior,whether this is due to a diminished role of 2-arachydonoylglycerol and/or anandamide re-mains unclear. Although it might seem intuitivethat both endocannabinoids are involved in

promoting dopamine signaling during rewardseeking, we now know that this is not the case.On the contrary, multiple studies using phar-macological tools that specifically increaseanandamide levels report that these compoundsreduce the potency of cues to motivate drug-seeking behavior (Scherma et al. 2008; Forgetet al. 2009; Gamaleddin et al. 2011). To deter-mine whether such compounds reduce cue-evoked dopamine release, Cheer and colleagues(Oleson et al. 2012) tested the effects of VDM11(a drug that selectively increases anandamidelevels in the brain) (Van Der Stelt et al. 2006)under similar behavioral conditions to those inwhich rimonabant effectively decreased cue-evoked dopamine release. As was found follow-ing rimonabant treatment, VDM11 uniformlydecreased cue-evoked dopamine concentra-tions and reward seeking. Figure 4 illustratesthe effects of VDM11 on accumbal dopamineconcentrations across trials as a representativeanimal is responding for brain stimulation re-ward in a cued intracranial self-stimulation task.Two dopamine peaks are evident per trial. Thefirst corresponds to the conditioned cue, andthe second results from the animal respondingfor the brain stimulation reward. Note that inresponse to VDM11, cue-evoked dopamine re-lease decreased, whereas the electrically evokeddopamine peak drifts away from cue presenta-tion and eventually off the temporal scale. TheFigure 4 inset depicts a magnified surface plotshowing the effects of VDM11 on cue-evokeddopamine events alone. These data support thenotion that anandamide decreases dopaminesignaling during reward seeking. Moreover,these data indirectly suggest that 2-arachydo-noylglycerol is the primary endocannabinoidinvolved in modulating cue-evoked dopaminerelease during reward-seeking behavior. In thiscase, it is possible that anandamide, which is apartial agonist for CB1 receptors, functions as acompetitive antagonist in the presence of 2-arachydonoylglycerol, which is a full agonist atCB1 receptors (Howlett and Mukhopadhyay2000). This conclusion is consistent with theaforementioned observation that 2-arachydo-noylglycerol is the primary endocannabinoidinvolved in mediating synaptic plasticity in



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multiple brain regions (Melis et al. 2004; Tani-mura et al. 2010).

CONCLUDING REMARKS

Based on the evidence presented herein, com-monly abused cannabinoids, such as D9-tetra-hydrocannabinol, affect the mesolimbic do-pamine system similarly to other commondrugs of abuse. It is very likely that repeatedexposures to D9-tetrahydrocannabinol mightresult in neuroadaptations, not only to the mes-olimbic dopamine system, but also to down-stream targets that are critically involved in thedevelopment of drug addiction. Regarding theendocannabinoid system, we are still in a dis-covery phase. Little is known concerning the

relative contributions of specific endocannabi-noids or their exact signaling mechanisms. Weare, however, aware of compelling new evidenceshowing that the endocannabinoid system is ca-pable of modulating the mesolimbic dopaminesystem and its potential impact in disorders ofmotivation. Future studies must be conductedto dissect the precise roles of endocannabinoidsin this modulation to minimize side effects andhow they influence dopamine transmission inanimal models.

ACKNOWLEDGMENTS

This work is supported by NIH grantsR01DA022340 and R01DA025890 (to J.F.C.)and F32DA032266 (to E.B.O.).

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Figure 4. Anandamide decreases cue-evoked dopamine concentrations and reward seeking. A representativesurface plot shows changes in dopamine concentration (z-axis) occurring across trials (y-axis) while respondingis maintained by brain stimulation reward in a cued intracranial self-stimulation task. VDM11, a drug thatselectively increases the endocannabinoid anandamide, dose-dependently decreased phasic dopamine eventsoccurring in response to a reward-predictive cue. As the cue-evoked dopamine concentrations decreased, thebehavioral response for brain-stimulation reward shifted away from the conditioned cue. (Figure constructedfrom data by Oleson et al. 2012.)



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REFERENCES

Aceto MD, Scates SM, Lowe JA, Martin BR. 1995. Canna-binoid precipitated withdrawal by the selective cannabi-noid receptor antagonist, SR 141716A. Eur J Pharmacol282: R1–R2.

Aceto MD, Scates SM, Lowe JA, Martin BR. 1996. Depen-dence on D9-tetrahydrocannabinol: Studies on precipi-tated and abrupt withdrawal. J Pharmacol Exp Ther 278:1290–1295.

Aceto MD, Scates SM, Martin BB. 2001. Spontaneous andprecipitated withdrawal with a synthetic cannabinoid,WIN 55212-2. Eur J Pharmacol 416: 75–81.

Alger BE, Kim J. 2011. Supply and demand for endocanna-binoids. Trends Neurosci 34: 304–315.

Aragona BJ, Cleaveland NA, Stuber GD, Day JJ, Carelli RM,Wightman RM. 2008. Preferential enhancement of dop-amine transmission within the nucleus accumbens shellby cocaine is attributable to a direct increase in phasicdopamine release events. J Neurosci 28: 8821–8831.

Budney AJ, Hughes JR. 2006. The cannabis withdrawal syn-drome. Curr Opin Psychiatry 19: 233–238.

Budney AJ, Novy PL, Hughes JR. 1999. Marijuana with-drawal among adults seeking treatment for marijuanadependence. Addiction 94: 1311–1322.

Castaneda E, Moss DE, Oddie SD, Whishaw IQ. 1991. THCdoes not affect striatal dopamine release: Microdialysis infreely moving rats. Pharmacol Biochem Behav 40: 587–591.

Cheer JF, Marsden CA, Kendall DA, Mason R. 2000. Lack ofresponse suppression follows repeated ventral tegmentalcannabinoid administration: An in vitro electrophysio-logical study. Neuroscience 99: 661–667.

Cheer JF, Wassum KM, Heien ML, Phillips PE, WightmanRM. 2004. Cannabinoids enhance subsecond dopaminerelease in the nucleus accumbens of awake rats. J Neurosci24: 4393–4400.

Cheer JF, Wassum KM, Sombers LA, Heien ML, Ariansen JL,Aragona BJ, Phillips PE, Wightman RM. 2007. Phasicdopamine release evoked by abused substances requirescannabinoid receptor activation. J Neurosci 27: 791–795.

Chen JP, Paredes W, Li J, Smith D, Lowinson J, Gardner EL.1990. D9-Tetrahydrocannabinol produces naloxone-blockable enhancement of presynaptic basal dopamineefflux in nucleus accumbens of conscious, freely-movingrats as measured by intracerebral microdialysis. Psycho-pharmacology (Berl) 102: 156–162.

Chen JP, Paredes W, Lowinson JH, Gardner EL. 1991. Strain-specific facilitation of dopamine efflux by D9-tetrahydro-cannabinol in the nucleus accumbens of rat: An in vivomicrodialysis study. Neurosci Lett 129: 136–180.

Chen J, Marmur R, Pulles A, Paredes W, Gardner EL. 1993.Ventral tegmental microinjection of D9-tetrahydrocan-nabinol enhances ventral tegmental somatodendriticdopamine levels but not forebrain dopamine levels: Evi-dence for local neural action by marijuana’s psychoactiveingredient. Brain Res 621: 65–70.

Childress AR, McLellan AT, Ehrman R, O’Brien CP. 1988.Classically conditioned responses in opioid and cocainedependence: A role in relapse. NIDA Res Monogr 84: 25–43.

Childress AR, Hole AV, Ehrman RN, Robbins SJ, McLellanAT, O’Brien CP. 1993. Cue reactivity and cue reactivityinterventions in drug dependence. NIDA Res Monogr137: 73–95.

Devane WA, Dysarz FA, Johnson MR, Melvin LS, HowlettAC. 1988. Determination and characterization of a can-nabinoid receptor in rat brain. Mol Pharmacol 34: 605–613.

Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA,Griffin G, Gibson D, Mandelbaum A, Etinger A, Me-choulam R. 1992. Isolation and structure of a brain con-stituent that binds to the cannabinoid receptor. Science258: 1946–1949.

Diana M, Muntoni AL, Pistis M, Melis M, Gessa GL. 1999.Lasting reduction in mesolimbic dopamine neuronal ac-tivity after morphine withdrawal. Eur J Neurosci 11:1037–1041.

Di Chiara G, Imperato A. 1988. Drugs abused by humanspreferentially increase synaptic dopamine concentrationsin the mesolimbic system of freely moving rats. Proc NatlAcad Sci 85: 5274–5278.

Dreyer JK, Herrik KF, Berg RW, Hounsgaard JD. 2010. In-fluence of phasic and tonic dopamine release on receptoractivation. J Neurosci 30: 14273–14283.

Einhorn LC, Johansen PA, White FJ. 1988. Electrophysio-logical effects of cocaine in the mesoaccumbens dopa-mine system: Studies in the ventral tegmental area. J Neu-rosci 8: 100–112.

Epstein DH, Preston KL, Stewart J, Shaham Y. 2006. Towarda model of drug relapse: An assessment of the validity ofthe reinstatement procedure. Psychopharmacology (Berl)189: 1–16.

Forget B, Coen KM, Le Foll B. 2009. Inhibition of fatty acidamide hydrolase reduces reinstatement of nicotine seek-ing but not break point for nicotine self-administrationcomparison with CB 1 receptor blockade. Psychopharma-cology 205: 613–624.

French ED. 1997. D9-Tetrahydrocannabinol excites rat VTAdopamine neurons through activation of cannabinoidCB1 but not opioid receptors. Neurosci Lett 226: 159–162.

French ED, Dillon K, Wu X. 1997. Cannabinoids excitedopamine neurons in the ventral tegmentum and sub-stantia nigra. Neuroreport 8: 649–652.

Freund TF, Katona I, Piomelli D. 2003. Role of endogenouscannabinoids in synaptic signaling. Physiol Rev 83: 1017–1066.

Gamaleddin I, Guranda M, Goldberg SR, Le Foll B. 2011.The selective anandamide transport inhibitor VDM11attenuates reinstatement of nicotine seeking induced bynicotine associated cues and nicotine priming, but doesnot affect nicotine-intake. Br J Pharmacol 164: 1652–1660.

Gaoni Y, Mechoulam R. 1964. Isolation, structure, and par-tial synthesis of an active constituent of hashish. J AmChem Soc 86: 1646–1647.

Gardner EL. 2002. Addictive potential of cannabinoids: Theunderlying neurobiology. Chem Phys Lipids 121: 267–290.



ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



Gardner EL. 2005. Endocannabinoid signaling system andbrain reward: Emphasis on dopamine. Pharmacol Bio-chem Behav 81: 263–284.

Gardner EL, Lowinson JH. 1991. Marijuana’s interactionwith brain reward systems: Update 1991. Pharmacol Bio-chem Behav 40: 571–580.

Gessa GL, Melis M, Muntoni AL, Diana M. 1998. Cannabi-noids activate mesolimbic dopamine neurons by an ac-tion on cannabinoid CB1 receptors. Eur J Pharmacol 341:39–44.

Gonon F. 1988. Nonlinear relationship between impulseflow and dopamine released by rat midbrain dopaminer-gic neurons as studied by in vivo electrochemistry. Neu-roscience 24: 19–28.

Grace AA. 1991. Phasic versus tonic dopamine release andthe modulation of dopamine system responsivity: A hy-pothesis for the etiology of schizophrenia. Neuroscience41: 1–24.

Haney M, Ward AS, Comer SD, Foltin RW, Fischman MW.1999. Abstinence symptoms following smoked marijua-na in humans. Psychopharmacology 141: 395–404.

Herkenham M, Lynn AB, de Costa BR, Richfield EK. 1991.Neuronal localization of cannabinoid receptors in thebasal ganglia of the rat. Brain Res 547: 267–274.

Hershkowitz M, Szechtman H. 1979. Pretreatment with D1-tetrahydrocannabinol and psychoactive drugs: Effects onuptake of biogenic amines and on behavior. Eur J Phar-macol 59: 267–276.

Howlett AC, Mukhopadhyay S. 2000. Cellular signal trans-duction by anandamide and 2-arachidonoylglycerol.Chem Phys Lipids 108: 53–70.

Hungund BL, Szakall I, Adam A, Basavarajappa BS, VadaszC. 2003. Cannabinoid CB1 receptor knockout mice ex-hibit markedly reduced voluntary alcohol consumptionand lack alcohol induced dopamine release in the nucleusaccumbens. J Neurochem 84: 698–704.

Jones RT, Benowitz N, Bachman J. 1976. Clinical studies ofcannabis tolerance and dependence. Ann NY Acad Sci282: 221–239.

Julian MD, Martin AB, Cuellar B, Rodriguez De Fonseca F,Navarro M, Moratalla R, Garcia-Segura LM. 2003. Neu-roanatomical relationship between type 1 cannabinoidreceptors and dopaminergic systems in the rat basal gan-glia. Neuroscience 119: 309–318.

Justinova Z, Munzar P, Panlilio L, Yasar S, Redhi G, Tanda G,Goldberg S. 2008. Blockade of THC-seeking behaviorand relapse in monkeys by the cannabinoid CB1-receptorantagonist rimonabant. Neuropsychopharmacology 33:2870–2877.

Justinova Z, Panlilio LV, Goldberg SR. 2009. Drug addiction.Curr Top Behav Neurosci 1: 309–346.

Koob GF. 2009. Neurobiological substrates for the dark sideof compulsivity in addiction. Neuropharmacology 56:18–31.

Koob GF, Sanna PP, Bloom FE. 1998. Neuroscience of ad-diction. Review. Neuron 21: 461–476.

Le Foll B, Goldberg S. 2004. Rimonabant, a CB1 antagonist,blocks nicotine-conditioned place preferences. Neurore-port 15: 2139–2143.

Lichtman AH, Martin BR. 2002. Marijuana withdrawal syn-drome in the animal model. J Clin Pharmacol 42: 20S–27S.

Lupica CR, Riegel AC. 2005. Endocannabinoid release frommidbrain dopamine neurons: A potential substrate forcannabinoid receptor antagonist treatment of addiction.Neuropharmacology 48: 1105–1116.

Malone DT, Taylor DA. 1999. Modulation by fluoxetine ofstriatal dopamine release following D9-tetrahydrocan-nabinol: A microdialysis study in conscious rats. Br JPharmacol 128: 21–26.

Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, BonnerTI. 1990. Structure of a cannabinoid receptor and func-tional expression of the cloned cDNA. Nature 346: 561–564.

Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Ka-minski NE, Schatz AR, Gopher A, Almog S, Martin BR,Compton DR. 1995. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to can-nabinoid receptors. Biochem Pharmacol 50: 83–90.

Melis M, Pistis M, Perra S, Muntoni AL, Pillolla G, Gessa GL.2004. Endocannabinoids mediate presynaptic inhibitionof glutamatergic transmission in rat ventral tegmentalarea dopamine neurons through activation of CB1 recep-tors. J Neurosci 24: 53–62.

Ng Cheong Ton JM, Gerhardt GA, Friedemann M, EtgenAM, Rose GM, Sharpless NS, Gardner EL. 1988. Theeffects of D9-tetrahydrocannabinol on potassium-evokedrelease of dopamine in the rat caudate nucleus: An in vivoelectrochemical and in vivo microdialysis study. Brain Res451: 59–68.

Oleson EB, Beckert MV, Morra JT, Lansink CS, Cachope R,Abdullah RA, Loriaux AL, Schetters D, Pattij T, RoitmanMF, et al. 2012. Endocannabinoids shape accumbal en-coding of cue-motivated behavior via CB1 receptor acti-vation in the ventral tegmentum. Neuron 73: 360–373.

Owesson-White CA, Ariansen J, Stuber GD, Cleaveland NA,Cheer JF, Wightman RM, Carelli RM. 2009. Neural en-coding of cocaine-seeking behavior is coincident withphasic dopamine release in the accumbens core and shell.Eur J Neurosci 30: 1117–1127.

Perra S, Pillolla G, Melis M, Muntoni AL, Gessa GL, Pistis M.2005. Involvement of the endogenous cannabinoid sys-tem in the effects of alcohol in the mesolimbic rewardcircuit: Electrophysiological evidence in vivo. Psycho-pharmacology (Berl) 183: 368–377.

Phillips PE, Stuber GD, Heien ML, Wightman RM, CarelliRM. 2003. Subsecond dopamine release promotes co-caine seeking. Nature 422: 614–618.

Pierce RC, Kumaresan V. 2006. The mesolimbic dopaminesystem: The final common pathway for the reinforcingeffect of drugs of abuse? Neurosci Biobehav Rev 30: 215–238.

Poddar MK, Dewey WL. 1980. Effects of cannabinoids oncatecholamine uptake and release in hypothalamic andstriatal synaptosomes. J Pharmacol Exp Ther 214: 63–67.

Ritz MC, Lamb RJ, Goldberg SR, Kuhar MJ. 1987. Cocainereceptors on dopamine transporters are related to self-administration of cocaine. Science 237: 1219–1223.

Roberts DC, Corcoran ME, Fibiger HC. 1977. On the role ofascending catecholaminergic systems in intravenous self-



ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



administration of cocaine. Pharmacol Biochem Behav 6:615–620.

Rossetti ZL, Hmaidan Y, Gessa GL. 1992. Marked inhibitionof mesolimbic dopamine release: A common feature ofethanol, morphine, cocaine and amphetamine absti-nence in rats. Eur J Pharmacol 221: 227–234.

Scherma M, Medalie J, Fratta W, Vadivel SK, Makriyannis A,Piomelli D, Mikics E, Haller J, Yasar S, Tanda G. 2008. Theendogenous cannabinoid anandamide has effects on mo-tivation and anxiety that are revealed by fatty acid amidehydrolase (FAAH) inhibition. Neuropharmacology 54:129–140.

Solinas M, Goldberg SR, Piomelli D. 2008. The endocanna-binoid system in brain reward processes. Br J Pharmacol154: 369–383.

Sombers LA, Beyene M, Carelli RM, Wightman RM. 2009.Synaptic overflow of dopamine in the nucleus accumbensarises from neuronal activity in the ventral tegmentalarea. J Neurosci 29: 1735–1742.

Spanagel R, Weiss F. 1999. The dopamine hypothesis ofreward: Past and current status. Trends Neurosci 22:521–527.

Szabo B, Siemes S, Wallmichrath I. 2002. Inhibition ofGABAergic neurotransmission in the ventral tegmentalarea by cannabinoids. Eur J Neurosci 15: 2057–2061.

Tanda G, Pontieri FE, Di Chiara G. 1997. Cannabinoid andheroin activation of mesolimbic dopamine transmissionby a common m1 opioid receptor mechanism. Science276: 2048–2050.

Tanda G, Loddo P, Di Chiara G. 1999. Dependence of mes-olimbic dopamine transmission on D9-tetrahydrocan-nabinol. Eur J Pharmacol 376: 23–26.

Tanimura A, Yamazaki M, Hashimotodani Y, UchigashimaM, Kawata S, Abe M, Kita Y, Hashimoto K, Shimizu T,Watanabe M, et al. 2010. The endocannabinoid 2-arach-idonoylglycerol produced by diacylglycerol lipase a me-diates retrograde suppression of synaptic transmission.Neuron 65: 320–327.

Todd A. 1946. Hashish. Experientia 2: 55–60.

Tsou K, Patrick SL, Walker JM. 1995. Physical withdrawal inrats tolerant to D9-tetrahydrocannabinol precipitated by

a cannabinoid receptor antagonist. Eur J Pharmacol 280:R13–R15.

Van Der Stelt M, Mazzola C, Esposito G, Matias I, PetrosinoS, Filippis DD, Micale V, Steardo L, Drago F, Iuvone T.2006. Endocannabinoids andb-amyloid-induced neuro-toxicity in vivo: Effect of pharmacological elevation ofendocannabinoid levels. Cell Mol Life Sci 63: 1410–1424.

Vries T, Schoffelmeer A. 2005. Cannabinoid CB1 receptorscontrol conditioned drug seeking. Trends Pharmacol Sci26: 420–426.

Weiss F, Markou A, Lorang MT, Koob GF. 1992. Basal extra-cellular dopamine levels in the nucleus accumbens aredecreased during cocaine withdrawal after unlimited-ac-cess self-administration. Brain Res 593: 314–318.

Weiss F, Parsons LH, Schulteis G, Hyyti P, Lorang MT, BloomFE, Koob GF. 1996. Ethanol self-administration restoreswithdrawal-associated deficiencies in accumbal dopa-mine and 5-hydroxytryptamine release in dependentrats. J Neurosci 16: 3474–3485.

Weiss F, Ciccocioppo R, Parsons LH, Katner S, Liu X, Zor-rilla EP, Valdez GR, Ben-Shahar O, Angeletti S, RichterRR. 2001. Compulsive drug-seeking behavior and re-lapse. Neuroadaptation, stress, and conditioning factors.Ann NY Acad Sci 937: 1–26.

Wheeler RA, Carelli RM. 2009. Dissecting motivational cir-cuitry to understand substance abuse. Neuropharmacol-ogy 56: 149–159.

Wickelgren I. 1997. Marijuana: Harder than thought? Sci-ence 276: 1967–1968.

Wilson RI, Nicoll RA. 2001. Endogenous cannabinoids me-diate retrograde signalling at hippocampal synapses. Na-ture 410: 588–592.

Wilson RI, Nicoll RA. 2002. Endocannabinoid signaling inthe brain. Science 296: 678–682.

Wise RA, Bozarth MA. 1985. Brain mechanisms of drugreward and euphoria. Psychiatr Med 3: 445–460.

Wu X, French ED. 2000. Effects of chronic D9-tetrahydro-cannabinol on rat midbrain dopamine neurons: An elec-trophysiological assessment. Neuropharmacology 39:391–398.



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2012; doi: 10.1101/cshperspect.a012229Cold Spring Harb Perspect Med Erik B. Oleson and Joseph F. Cheer SeekingA Brain on Cannabinoids: The Role of Dopamine Release in Reward

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